DESCRIPTION (Applicant's abstract): We will determine the contributions of the lung and the chest wall muscles to three key determinants of systemic oxygen transport during exercise, namely, cardiac output, locomotor muscle blood flow and arterial O2 content. First, we will test the hypothesis that the work of breathing (Wv) during exercise is an important determinant of the vascular resistance (VRL), blood flow (QL) and therefore the VO2 of the working limb locomotor muscles (VO2L) - especially at maximum exercise intensity in health and in patients with chronic heart failure. We will also determine the effects of exercise intensity, of hypoxia and of respiratory muscle training on the influence of Wv on QL. Microneurography will be used to assess if increased Wv affects limb muscle blood flow via reflexly triggered augmentation of muscle sympathetic nerve activity. A second aim concerned with cardiopulmonary interactions during exercise will address if respiratory-induced negative intrathoracic pressure during exercise compromises stroke volume and cardiac output in the healthy heart as well as the heart in failure. Thirdly, we will determine if the healthy female - of widely varying VO2max and age - has an increased susceptibility to exercise-induced diffusion limitation causing arterial hypoxemia (EIH), and also to expiratory flow limitation and to increased Wv. Our preliminary data support these proposals of a significant compromising effect of Wv on locomotor muscle blood flow at max exercise and of a strong influence of gender on exercise-induced arterial hypoxemia via diffusion limitation. Finally, we will quantify the relative contributions of Wv (via effects on QL) and diffusion limitation (via EIH) to the limitation of VO2max and exercise endurance performance with special emphasis on the highly fit, the female, healthy aging and the patient with chronic heart failure.